The goal of this proposal is to establish the efficacy of contulakin-G (CGX-1160), a newly discovered analgesic conopeptide for the treatment of chronic pain. Currently chronic pain is treated with a variety of analgesic and adjuvant drugs including: opioids, tricyclic antidepressants, anticonvulsants, and local anesthetics. A significant number of patients, particularly those suffering from neuropathic pain, are refractory to all of the currently available drugs. Furthermore, all of these compounds have significant, dose- and treatment-limiting side effects. Preliminary data suggest that CGX-1160 is an extremely potent analgesic in animal models of persistent pain following intrathecal administration, with a wide separation between efficacy and toxicity, and may represent an alternative therapy for intractable pain. In phase I we will demonstrate the efficacy of CGX-1160 in a broad range of animal pain models including: acute, persistent inflammatory, chronic inflammatory, and neuropathic pain. A series of closely related analogs will be synthesized and compared to the native conopeptide for their in vivo efficacy, and resistance to endogenous peptidases. We will attempt to determine the specific mechanism of action through in vivo and in vitro pharmacological methods. We will also compare the toxicity profile of this compound with morphine. These studies will determine a behavioral therapeutic index for the compounds tested. This will determine which of the analogs will be further characterized in formal toxicology testing. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE